Granules containing acid-unstable chemical in large amount

ABSTRACT

It is intended to provide preparations such as capsules containing an acid-unstable medicament (in particular, a benzimidazole compound having an antiulcer effect, etc.) at a high concentration which are prepared by using about 12% by weight or more (based on the total granules) of the acid-unstable chemical and blending a basic inorganic salt therewith to give granules of about 600 μm or more in the average particle size.

TECHNICAL FIELD

The present invention relates to stabilized granules, which comprises ahigh content of an acid-unstable medicament, in particular, abenzimiadzole compound useful as an antiulcer agent and a basicinorganic substance.

BACKGROUND ART

Since benzimidazole compounds such as lansoprazole, omeprazole andrabeprazole have gastric acid secretion inhibitory activity, gastricmucoca protecting activity, etc., they are widely used as a peptic ulcertreating agent.

However, these compounds are inferior in stability, and are unstable tohumidity, temperature and light. In particular, they are unstable toacids and, when formulated into an aqueous solution or a suspension,they become extremely unstable with lowering of pH.

In addition, stability in the form of preparations, i.e., tablets,powders, fine granules, capsules, etc. becomes lower than that of thecompounds alone because of their strong interaction with othercomponents in formulated preparations, and color change or degradationis observed upon production or storage of the preparations. In order tostabilize them, JP 62-277322 A discloses enteric granules, enteric finegranules, etc. obtained by blending a stabilizing agent composed of abasic inorganic salt of magnesium and/or calcium, followed by entericcoating.

Meanwhile, it is necessary to apply an enteric coating to abenzimidazole compound because the compound has such properties that itis hardly soluble in water and is unstable to acids. An enteric coatingdoes not dissolve in a stomach containing a relatively larger amount ofwater, but dissolves in a small intestine containing a smaller amount ofwater, whereby a benzimidazole compound is dissolved and absorbed. Thatis, since a composition containing a benzimidazole compound is requiredto be rapidly disintegrated in a small intestine, granules which have alarger surface area, and which are more easily and rapidly disintegratedor dissolved than tablets are considered to be more desired.

In Examples specifically disclosed in JP 62-277322 A, the content ofbenzimidazole compound is about 6.3 to 11.5% based on the total entericgranules, and the capsule in which the granules are filled is No. 1 or2. Pharmacy Vol. 50(3) 230-238 (1990) reports that smaller capsules aremore easily administered in view of an appearance organoleptic test, anda limit of a capsule size which can be easily administered is No. 3.Then, No. 1 or 2 capsule may reduce compliance of patients, inparticular, elderly patients who have difficulty in swallowing.

OBJECTS OF THE INVENTION

In order to facilitate administration to patients, in particular,elderly or pediatric patients who have difficulty in swallowing, and toimprove compliance, an object of the present invention is to producestable enteric granules which comprises an acid-unstable medicamentincluding a benzimidazole compound in a high content and a basicinorganic salt, and to render a size of a capsule in which the entericgranules are filled suitable for easy administration.

SUMMARY OF THE INVENTION

The present inventors have found that, in granules which contain anacid-unstable medicament, in particular, a benzimidazole compound and abasic inorganic salt as a stabilizing agent, and which are coated withan enteric layers or agents, the acid-unstable medicament can bestabilized even in high concentration and a high content, and can beeasily administered to patients with improved compliance by adjusting ablending ratio of the basic inorganic salt to the acid-unstablemedicament and an average particle size properly. The present inventorshave further studied and, as a result, the present invention has beencompleted.

That is, the present invention provides:

(1) Granules comprising a principal ingredient layer containing anacid-unstable medicament in an amount of about 12% by weight or morebased on the total granules; an intermediate coating layer which isformed on the principal ingredient layer; and an enteric coating layerwhich is formed on the intermediate coating layer; wherein said granulescontain a basic inorganic salt, and have an average particle size ofabout 600 μm or more;

(2) The granules according to the above (1), wherein the basic inorganicsalt is a magnesium salt or a calcium salt;

(3) The granules according to the above (1), wherein the acid-unstablemedicament is a proton pump inhibitor (PPI);

(4) The granules according to the above (3), wherein the PPI is abenzimidazole compound represented by the formula (I):

wherein ring A is an optionally substituted benzene ring, R¹, R² and R³are the same or different, and represent a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted alkoxy group, or anoptionally substituted amino group, and Y represents a nitrogen atom orCH, or a salt thereof;

(5) The granules according to the above (3), wherein the PPI islansoprazole, omeprazole, rabeprazole, pantoprazole, leminoprazole,tenatoprazole (TU-199), or an optically active isomer thereof, or apharmaceutically acceptable salt thereof;

(6) The granules according to the above (3), wherein the PPI islansoprazole, or an optically active isomer thereof, or apharmaceutically acceptable salt thereof;

(7) The granules according to the above (4), wherein the basic inorganicsalt is contained in the principal ingredient layer in an amount ofabout 0.2 part by weight to about 0.6 part by weight based on 1 part byweight of the benzimidazole compound;

(8) The granules according to the above (1) which are granules having acore, wherein the principal ingredient layer is formed on the corecomprising at least one material selected from sucrose, starch, lactoseand crystalline cellulose;

(9) The granules according to the above (1), wherein the enteric coatinglayer contains an enteric water-soluble polymer;

(10) The granules according to the above (9), wherein the entericwater-soluble polymer is a methacrylic acid copolymer;

(11) The granules according to the above (1), wherein an averageparticle size of the granules is about 1000 μm to about 2000 μm;

(12) The granules according to the above (4), wherein the benzimidazolecompound is contained in an amount of about 12% by weight to about 40%by weight based on the total granules;

(13) A granular preparation, a capsule, a tablet, an effervescentpreparation or a suspension comprising the granules according to theabove (1);

(14) Granules comprising a principal ingredient layer containing a PPIin an amount of about 12% by weight to about 40% by weight based on thetotal granules, and one or more basic inorganic salts selected from thegroup consisting of basic salts of a sodium salt, a potassium salt, analuminum salt, a magnesium salt and a calcium salt in an amount of about0.2 part by weight to about 0.6 part by weight based on 1 part by weightof the PPI; an intermediate coating layer which is formed on theprincipal ingredient layer; and an enteric coating layer which is formedon the intermediate coating layer, and having an average particle sizeof about 1000 μm to about 2000 μm;

(15) A granular preparation, a capsule or a tablet comprising thegranules according to the above (14);

(16) The preparation according to the above (15), which is a preparationfor treating or preventing peptic ulcer, Zollinger-Ellison syndromes,gastritis, reflux esophagitis, symptomatic gastroesophageal refluxdisease (symptomatic GERD), NUD (non ulcer dyspepsia), stomach cancer,gastric MALT lymphoma, ulcer resulting from nonsteroidalantiinflammatory medicaments, or excess stomach acid or ulcer due topost-operation stress, a preparation for eradicating Helicobacterpylori, or a preparation for suppressing upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasion stress;

(17) Granules comprising a principal ingredient layer containinglansoprazole or an optically active isomer (R isomer) thereof in anamount of about 14% by weight to about 20% by weight based on the totalgranules, and one or more basic inorganic salts selected from the groupconsisting of basic salts of magnesium and calcium in an amount of about0.2 part by weight to about 0.4 part by weight based on 1 part by weightof lansoprazole or an optically active isomer (R isomer) thereof; anintermediate coating layer which is formed on the principal ingredientlayer; and an enteric coating layer which is formed on the intermediatecoating layer, and having an average particle size of 1000 μm to about2000 μm;

(18) The granules according to the above (17), wherein the basicinorganic salt is magnesium carbonate;

(19) No. 3 to 5 capsules comprising 30 mg of lansoprazole per onecapsule;

(20) The capsule according to the above (19), wherein the granulesaccording to the above (17) are filled;

(21) No. 4 to 5 capsules comprising 15 mg of lansoprazole per onecapsule;

(22) The capsule according to the above (21), wherein the granulesaccording to the above (17) are filled;

(23) No. 1 to 3 capsules comprising 60 mg of lansoprazole or anoptically active isomer (R isomer) thereof per one capsule;

(24) The capsule according to the above (23), wherein the granuleaccording to the above (17) is filled;

(25) No. 2 to 4 capsules comprising 40 mg of an optically active isomer(R isomer) of lansoprazole per one capsule;

(26) The capsule according to the above (25), wherein the granulesaccording to the above (17) are filled;

(27) No. 3 to 5 capsules comprising 30 mg of an optically active isomer(R isomer) of lansoprazole per capsule;

(28) The capsule according to the above (27), wherein the granules asdefined in the above (17) are filled; and

(29) A pharmaceutical composition which is a combination of anantimicrobial agent and the granules according to the above (3).

DETAILED DESCRIPTION OF THE INVENTION

The granules of the present invention are characterized in that theycontain an acid-unstable medicament in high concentration, and have, atleast, a principal ingredient layer, an intermediate coating layer whichis formed on the principal ingredient layer, and further an entericcoating layer which is formed on the intermediate coating layer. Theacid-unstable medicament as the principal active ingredient is containedin the principal ingredient layer but, structurally, the principalingredient layer may have such a construction that it further has a coretherein. And, the intermediate coating layer which is formed between theprincipal ingredient layer and the enteric coating layer has astabilization function of the acid-unstable medicament contained in theprincipal ingredient layer by avoiding direct contact between theprincipal ingredient layer and the enteric coating layer.

The acid-unstable medicament in the present invention is notspecifically limited, and may any medicaments which become unstable whenexposed to an acid. Examples of such acid-unstable medicament includePPI having antiulcer activity, inter alia, benzimidazole compounds,imidazopyridine compounds, erythromycin antimicrobial compounds, andantiinflammatory enzymes such as serrapeptase, semialkaline proteinase,etc. and the like. In particular, the present invention is suitable forPPI such as benzimidazole compounds and imidazopyridine compounds havingantiulcer activity. Hereinafter, the present invention will beillustrated with respect to benzimidazole compounds, but the presentinvention is not limited thereto, and can be similarly applied to otheracid-unstable medicaments.

In the benzimidazole compounds having antiulcer activity used in thepresent invention, a preferred one is a compound of the above formula(I) in which ring A is a benzene ring which may be substituted with ahalogen atom, an optionally halogenated C₁₋₄ alkyl group, an optionallyhalogenated C₁₋₄ alkoxy group and a 5- or 6-membered heterocyclic group,R¹ is a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkoxygroup or a di-C₁₋₆ alkylamino group, R² is a hydrogen atom, a C₁₋₆alkoxy-C₁₋₆ alkoxy group or an optionally halogenated C₁₋₆ alkoxy group,R³ is a hydrogen atom or a C₁₋₆ alkyl group, and Y is a nitrogen atom.

The particularly preferred one is a compound represented by the formula(Ia):

wherein R¹ represents a C₁₋₃ alkyl group or a C₁₋₃ alkoxy group, R²represents a C₁₋₃ alkoxy group which may be halogenated or substitutedwith a C₁₋₃ alkoxy group, R³ represents a hydrogen atom or a C₁₋₃ alkylgroup, and R⁴ represents a hydrogen atom, an optionally halogenated C₁₋₃alkoxy group or a pyrrolyl group (e.g. 1-, 2- or 3-pyrrolyl group).

In the above formula (Ia), the particularly preferred one is a compoundin which R¹ is a C₁₋₃ alkyl group, R² is an optionally halogenated C₁₋₃alkoxy group, R³ is a hydrogen atom, and R⁴ is a hydrogen atom or anoptionally halogenated C₁₋₃ alkoxy group.

Examples of the “substituent” in the “optionally substituted benzenering” represented by ring A in the compound represented by the aboveformula (I) [hereinafter, referred to as compound (I)] include a halogenatom, a cyano group, a nitro group, an optionally substituted alkylgroup, a hydroxy group, an optionally substituted alkoxy group, an arylgroup, an aryloxy group, a carboxy group, an acyl group, an acyloxygroup, a 5- to 10-membered heterocyclic group, etc. and the benzene ringmay be substituted with about one to three these substituents. When thenumber of substituents is 2 or more, respective substituents may be thesame or different. Among these substituents, a halogen atom, anoptionally substituted alkyl group, an optionally substituted alkoxygroup, etc. is preferred.

Examples of the halogen atom include fluorine, chlorine and bromineatoms, etc. Inter alia, fluorine is preferred.

Examples of the “alkyl group” in the “optionally substituted alkylgroup” include C₁₋₇ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl groups,etc.). As the “substituent” in the “optionally substituted alkyl group”,there can be exemplified a halogen atom, a hydroxy group, C₁₋₆ alkoxygroups (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), C₁₋₆alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl groups, etc.), a carbamoyl group, etc. and the number ofthese substituents may be about 1 to 3. When the number of substituentsis 2 or more, respective substituents may be the same or different.

Examples of the “alkoxy group” in the “optionally substituted alkoxygroup” include C₁₋₆ alkoxy groups (e.g. methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, pentoxy, etc.). Examples of the“substituent” in the “optionally substituted alkoxy group” include thesame “substituents” as those for the above “substituent” in the“optionally substituted alkyl group”, and the number of substituents isalso the same as defined above.

Examples of the “aryl group” include C₆₋₁₄ aryl groups (e.g. phenyl,1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl groups, etc.) and the like.

Examples of the “aryloxy group” include C₆₋₁₄ aryloxy groups (e.g.phenyloxy, 1-naphthyloxy, 2-naphthyloxy groups, etc.) and the like.

Examples of the “acyl group” include formyl, alkylcarbonyl,alkoxycarbonyl, carbamoyl, alkylcarbamoly, alkylsulfinyl, alkylsulfonylgroups, and the like.

Examples of the “alkylcarbonyl group” include C₁₋₆ alkyl-carbonyl groups(e.g. acetyl, propionyl groups, etc.) and the like.

Examples of the “alkoxycarbonyl group” include C₁₋₆ alkoxy-carbonylgroups (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl groups, etc.) and the like.

Examples of the “alkylcarbamoyl group” include N—C₁₋₆ alkyl-carbamoylgroups (e.g. methylcarbamoyl, ethylcarbamoyl groups, etc.), N,N-di-C₁₋₆alkyl-carbamoyl groups (e.g. N,N-dimethycarbamoyl, N,N-diethylcarbamoylgroups, etc.) and the like.

Examples of the “alkylsulfinyl group” include C₁₋₇ alkylsulfinyl groups(e.g. methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinylgroups, etc.).

Examples of the “alkylsulfonyl group” include C₁₋₇ alkylsulfonyl groups(e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonylgroups, etc.).

Examples of the “acyloxy group” include an alkylcarbonyloxy group, analkoxycarbonyloxy group, a carbamoyloxy group, an alkylcarbamoyloxygroup, an alkylsulfinyloxy group, an alkylsulfonyloxy group and thelike.

Examples of the “alkylcarbonyloxy group” include C₁₋₆ alkyl-carbonyloxygroups (e.g. acetyloxy, propionyloxy groups, etc.) and the like.

Examples of the “alkoxycarbonyloxy group” include C₁₋₆alkoxy-carbonyloxy groups (e.g. methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy groups, etc.) and the like.

Examples of the “alkylcarbamoyloxy group” include C₁₋₆alkyl-carbamoyloxy groups (e.g. methylcarbamoyloxy, ethylcarbamoyloxygroups, etc.) and the like.

Examples of the “alkylsulfinyloxy group” include C₁₋₇ alkylsulfinyloxygroups (e.g. methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyloxy,isopropylsulfinyloxy groups, etc.) and the like.

Examples of the “alkylsulfonyloxy group” include C₁₋₇ alkylsulfonyloxygroups (e.g. methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy,isopropylsulfonyloxy groups, etc.).

Examples of the “5- to 10-membered heterocyclic group” include 5- to10-membered (preferably 5- or 6-membered) heterocyclic groups containing1 or more (for example, 1 to 3) hetero atom(s) selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms, andspecific examples thereof include a 2- or 3-thienyl group, a 2-, 3- or4-pyridyl group, a 2- or 3-furyl group, a 1-, 2- or 3-pyrrolyl group, a2-, 3-, 4-, 5- or 8-quinolyl group, a 1-, 3-, 4- or 5-isoquinolyl group,and a 1-, 2- or 3-indolyl group and the like. Among them, a preferredone is a 5- or 6-membered heterocyclic group such as a 1-, 2- or3-pyrrolyl group, etc.

Preferably, ring A is a benzene ring optionally substituted with 1 or 2substituent(s) selected from a halogen atom, an optionally halogenatedC₁₋₄ alkyl group, an optionally halogenated C₁₋₄ alkoxy group and a 5-or 6-membered heterocyclic group.

Examples of the “optionally substituted alkyl group” represented by R¹,R² or R³ include the above “optionally substituted alkyl group”described as the substituent for the above ring A.

Examples of the “optionally substituted alkoxy group” represented by R¹,R² or R³ include the above “optionally substituted alkoxy group”described as the substituent for the above ring A.

Examples of the “optionally substituted amino group” represented by R¹,R² or R³ include an amino group, mono-C₁₋₆ alkylamino groups (e.g.methylamino, ethylamino, etc.), mono-C₆₋₁₄ arylamino groups (e.g.phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C₁₋₆ alkylaminogroups (e.g. dimethylamino, diethylamino, etc.), di-C₆₋₁₄ arylaminogroups (e.g. diphenylamino, etc.) and the like.

Preferred R¹ is a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆alkoxy-C₁₋₆ alkoxy group, or a di-C₁₋₆ alkylamino group. More preferredR² is a C₁₋₃ alkyl group or a C₁₋₃ alkoxy group.

Preferred R² is a hydrogen atom, a C₁₋₆ alkoxy-C₁₋₆ alkoxy group or anoptionally halogenated C₁₋₆ alkoxy group. More preferred R³ is a C₁₋₃alkoxy group which is halogenated or optionally substituted with a C₁₋₃alkoxy group.

Preferred R³ is a hydrogen atom, or a C₁₋₆ alkyl group. More preferredR⁴ is a hydrogen atom or a C₁₋₃ alkyl group (particularly a hydrogenatom).

Preferred Y is a nitrogen atom.

Specific examples of the compound (I) are the following compounds:

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-imidazole(lansoprazole),2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole,2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolesodium salt,5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,etc.

Among these compounds, in particular, lansoprazole, that is,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleis preferred.

Examples of the imidazopyridine compound include tenatoprazole and thelike.

The above compound (I) and imidazopyridine compound may be a racemicmodification or optically active isomers such as R-isomer and S-isomer.For example, optically active isomers such as(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(hereinafter, referred to as lansoprazole R isomer in some cases) and(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(hereinafter, referred to as lansoprazole S isomer in some cases) areparticularly suitable in the present invention. Usually, lansoprazole,lansoprazole R isomer, lansoprazole S isomer, etc. are preferably in theform of crystals. However, not only crystalline compounds but alsoamorphous compounds can be used because these compounds are stabilizedby formulating into preparations and, additionally, these compounds arefurther stabilized by blending a basic inorganic salt therein andproviding with an intermediate coating layer.

As a salt of the compound (I), a pharmaceutically acceptable salt ispreferred, and examples thereof include a salt with an inorganic base, asalt with an organic base, a salt with a basic amino acid and the like.

Preferred examples of the salt with an inorganic base include alkalimetal salts such as a sodium salt and a potassium salt; alkaline earthmetal salts such as a calcium salt and a magnesium salt; an ammoniumsalt and the like.

Preferred examples of the salt with an organic base include salts withalkylamines (trimethylamine, triethylamine, etc.), heterocyclic amines(pyridine, picoline, etc.), alkanolamines (ethanolamine, diethanolamine,triethanolamine, etc.), dicyclohexylamine, N,N′-dibenzylethylenediamineand the like.

Preferred examples of the salt with a basic amino acid include saltswith arginine, lysine, ornithine and the like.

Among these salts, an alkali metal salt or an alkaline earth metal saltis preferred. Inter alia, a sodium salt is preferred.

The compound (I) can be prepared by known per se methods, for example,the methods described in JP 61-50978 A, U.S. Pat. No. 4,628,098, JP10-195068 A, WO 98/21201, JP 52-62275 A, JP 54-141783 A and the like, orsimilar methods. The optically active compound (I) can be obtained by anoptical resolving method (fractionating recystallization method, chiralcolumn method, diastereomer method, method using microorganisms orenzymes and the like), asymmetric oxidation method and the like.Lansoprazole R isomer can also be prepared by a process described, forexample, in WO 00-78745, WO 01/83473 and the like.

As the benzimidazole compound having antiulcer activity used in thepresent invention, lansoprazole, omeprazole, rabeprazole, pantoprazole,leminoprazole, tenatoprazole (TU-199) and the like and optically activeisomers thereof as well as pharmaceutically acceptable salts arepreferred, and lansoprazole or an optically active isomer thereof, inparticular, an R isomer is more preferred.

The amount of PPI to be formulated in the present invention variesdepending on the kind of active component and dosage, and is forexample, about 12% by weight to about 40% by weight, preferably about12% by weight to about 20% by weight, more preferably about 14% byweight to about 20% by weight based on the total granules of the presentinvention. When PPI is the benzimidazole compound, in particularlansoprazole, the amount is about 14% by weight to about 20% by weight.

Examples of the basic inorganic salt used in the present inventioninclude basic inorganic salts of sodium, potassium, magnesium andcalcium. A preferred one is a basic inorganic salt of magnesium orcalcium. A more preferred one is a basic inorganic salt of magnesium.

Examples of the basic inorganic salt of sodium include sodium carbonate,sodium bicarbonate, sodium hydroxide and the like.

Examples of the basic inorganic salt of potassium include potassiumcarbonate, potassium bicarbonate, potassium hydroxide and the like.

Examples of the basic inorganic salt of magnesium include groundmagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide, magnesium aluminate metasilicate, magnesium silicate,magnesium aluminate, synthetic hydrotalcite [Mg₆Al₂(OH)₁₆.CO₃.4H₂O] andalumina magnesium hydroxide [2.5MgO.Al₂O₃.xH₂O], preferably, groundmagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide and the like.

Examples of the basic inorganic salt of calcium include precipitatedcalcium carbonate, calcium hydroxide and the like.

More preferred examples of the basic inorganic salt include groundmagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide and the like.

The basic inorganic salt used in the present invention may be a saltwhose 1% aqueous solution or suspension has basic pH (pH 7 or higher).

The basic inorganic salt may be formulated alone or in combination oftwo or more thereof, and the amount to be formulated is about 0.2 toabout 0.6 part by weight, preferably about 0.2 to about 0.4 part byweight based on 1 part by weight of PPI (benzimidazole compound, etc.).Inter alia, when PPI is lansoprazole or an optically active isomerthereof, preferably, the basic inorganic salt (preferably basicinorganic salt of magnesium or calcium, more preferably magnesiumcarbonate) is formulated in an amount of about 0.2 to about 0.4 part byweight based on 1 part by weight of PPI.

In the present invention, the “granules containing PPI (benzimidazolecompound, etc.) in an amount of about 12% by weight to about 40% byweight based on the total granules, containing the basic inorganic saltas a stabilizing agent, and having an average particle size of about 600μm or more” are preferred. When the particle size is smaller, it isdifficult to increase concentration of the benzimidazole compoundbecause a surface area becomes larger, which requires a larger amount ofan enteric layer or agent. That is, in the present invention, it hasbeen possible to decrease the amount of an enteric layer or agent bysetting the particle size of at least about 600 μm or more, therebyincreasing the concentration of the benzimidazole compound. The averageparticle size is about 600 to about 2500 μm. The more preferred averageparticle size is about 1000 to about 2000 μm. The granules may containparticles having a particle size of about 400 to about 3000 μm,preferably about 500 to about 2500 μm in so far as their averageparticle size, as a whole, is within the above range.

The particle size is measured by using a sieving method (Powder-Theoryand Application-, p475, 1979, Maruzen), and the average particle size iscalculated based on an average of meshes of corresponding sieves andweight distribution. That is, arithmetic averaging is performed based ona product of an average and each weight.

The granules of the present invention can be prepared by a knowngranulation method. Examples of the granulation method include a rotarygranulation method (e.g. centrifugal Fluid-bed granulation method), afluidized granulation method, an agitation granulation method (e.g.agitator fluidized granulation method) and the like. Among them, arotary granulation method and an agitation granulation method (agitatorfluidized granulation method) are preferred.

Specific examples of the rotary granulation method include CF apparatusmanufactured by Freund, etc. Specific examples of the agitator fluidizedgranulation method include methods using Spiral Flow manufactured byFreund, Multiplex manufactured by Powlex, New Malume manufactured byFuji Powdal and the like. A method for spraying a binder solution can beappropriately selected according to the kind of a granulator and, forexample, it may be any of a top spraying manner, a bottom sprayingmanner, a tangential spraying manner and the like.

Preferably, as described above, the granules of the present inventionhave a principal ingredient layer containing a principal ingredient, anintermediate coating layer which is formed on the principal ingredientlayer, and an enteric coating layer which is formed on the intermediatecoating layer.

For obtaining the granules having higher sphericity and narrowerparticle size distribution, in the present invention, the principalingredient layer is formed by coating cores composed of one or morematerials selected from sucrose, starch, lactose and microcrystallinecellulose with the benzimidazole compound. For example, granules havinga core may be prepared by the method described in JP 63-301816 A. Suchgranules can be obtained by a method of coating a sugar core with apowdery spreading mixture containing the benzimidazole compound havingantiulcer activity, the basic metal salt, an excipient, a disintegratingagent and the like, while spraying a binder solution ofhydroxypropylcellulose on the sugar cores. Examples of the core granulesinclude Nonpareil obtained by coating sucrose (75 parts by weight) withcorn starch (25 parts by weight) by a known per se method, sphericalcore granules using microcrystalline cellulose, etc. Alternatively, coregranules per se may be an active ingredient which becomes the aboveprincipal ingredient layer. An average particle size of the coregranules is generally 14 to 80 mesh.

Examples of the cores include a spherical granulated material of sucroseand starch, a spherical granulated material of crystalline cellulose, aspherical granulated material of crystalline cellulose and lactose, etc.

It is desirable that cores are as uniformly spherical as possible so asto reduce variability of coating.

The proportion of the coating layer to the cores can be selected fromwithin such a range that the dissolution property of the benzimidazolecompound and a particle size of the granules can be controlled. Forexample, the proportion is usually about 0.2 part by weight to about 5parts by weight, preferably about 0.1 part by weight to about 5 parts byweight based on 1 part by weight of the cores.

Coating layers with which the principal ingredient layer is coated maybe formed of plural layers. The plural coating layers may containvarious coating layers such as a coating layer for subcoating inaddition to the intermediate coating layer containing no medicament andthe enteric coating layer, and a particular combination of those coatinglayers may be appropriately selected.

In enteric coating granules containing an unstable principal ingredientsuch as the benzimidazole compound, etc., from a viewpoint ofimprovement in stability of the principal ingredient, it is preferableto arrange an intermediate coating layer between a principal ingredientlayer containing the benzimidazole compound, etc. and an enteric coatinglayer to block direct contact between the layers because the entericcoating layer component is an acidic substance.

Such an intermediate coating layer may be a coating layer which canprevent contact between the benzimidazole compound as a basis and anenteric coating layer, and the amount and material of the coating layerare not limited in so far as such an objective is achieved. For example,there is a layer in which a saccharide such as sucrose [refined whitesugar (pulverized (powdered sugar) or not pulverized), etc.], starchsugar such as corn starch, lactose, honey, sugar alcohol (D-mannitol,erythritol, etc.), etc. is appropriately formulated into a polymer basesuch as low-substituted hydroxypropylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose (e.g. TC-5, etc.), polyvinylpyrrolidone,polyvinyl alcohol, methylcellulose, hydroxyethylmethylcellulose and thelike. In addition, to the intermediate coating layer may beappropriately added an excipient (e.g. masking agent (titanium oxide,etc.), and an antistatic agent (titanium oxide, talc, etc.)) which areadded for formulating into a preparation as needed, as describedhereinafter.

The amount of the intermediate coating layer to be coated is usuallyabout 0.02 part by weight to about 1.5 parts by weight, preferably about0.05 part by weight to about 1 part by weight based on 1 part by weightof the granules containing, for example, benzimidazole. Coating can beperformed according to a conventional method. For example, preferably,these intermediate coating layer components are diluted with purifiedwater or the like to obtain a liquid, which is sprayed for coating. Atthis time, it is preferable to perform coating while spraying a binderagent of hydroxypropylcellulose or the like.

Examples of the “enteric coating layer” to be used for coating thegranules in the present invention include aqueous enteric polymer basessuch as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulosephthalate, hydroxymethylcellulose acetate succinate, methacrylic acidcopolymer, carboxymethylethylcellulose, shellac and the like,sustained-release bases such as ethyl acrylate-methacrylic acidcopolymer and the like, and plasticizers such as water-soluble polymer,triethyl citrate, polyethylene glycol, acetylated monoglyceride,triacetin, castor oil and the like. They can be used alone or incombination of two or more thereof.

The enteric coating layer is an enteric polymer base, preferably anaqueous enteric methacrylic acid copolymer.

The amount of the enteric coating layer to be coated is about 10% byweight to about 70% by weight, preferably about 10% by weight to about50% by weight, more preferably about 15% by weight to about 30% byweight based on the total amount of the granules before coating of theenteric coating.

Further, additives for formulating into pharmaceutical preparations canbe used, and examples thereof include excipients (e.g. glucose,fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose,sorbitol, corn starch, potato starch, wheat starch, rice starch,crystalline cellulose, anhydrous silicic acid, anhydrous calciumphosphate, precipitated calcium carbonate, calcium silicate, etc.),binders (e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodiumcarboxymethylcellulose, partial α-starch, α-starch, sodium alginate,pullulan, gum arabic powder, gelatin etc.), disintegrating agents (e.g.low-substituted hydroxypropylcellulose, carmellose, potassiumcarmellose, sodium carboxymethylstarch, sodium crosscarmellose,crosspovidone, hydroxypropylstarch, etc.), corrigents (e.g. citric acid,ascorbic acid, tartaric acid, malic acid, aspartame, potassiumacesulfame, sormatin, saccharin sodium, dipotassium glycyrrhizin, sodiumglutamate, sodium 5′-inosinate, sodium 5′-guanylate, etc.), surfactants(e.g. polysorbates (polysorbate 80, etc.),polyoxyethylene-polyoxypropylene copolymer, sodium laurylsulfate, etc.),flavors (e.g. lemon oil, orange oil, menthol, mint oil, etc.),lubricants (e.g. magnesium stearate, sucrose fatty acid esters, sodiumstearyl fumarate, stearic acid, talc, polyethylene glycol, etc.),colorants (e.g. titanium oxide, edible Yellow No.5, edible Blue No.2,iron sesquioxide, yellow iron sesquioxide etc.), antioxidants (e.g.sodium ascorbate, L-cysteine, sodium sulfite, etc.), masking agents(e.g. titanium oxide, etc.), antistatic agents (e.g. talc, titaniumoxide, etc.) and the like.

The particle size of raw materials used for these materials is notparticularly limited, but particles of about 500 μm or smaller arepreferred from a viewpoint of manufacturing properties andadministration properties.

The granules of the present invention can also be used in granularpreparations, capsules, tablets, effervescent preparations, suspensionsor the like.

From a viewpoint of easy handling, etc., capsules and tablets arepreferred. As capsules, gelatin capsules, HPMC capsules, pullulancapsules and the like may be used. When used as capsules, capsules ofNo.3 to No.5 in size are preferable for easy administration. Forexample, in case of a capsule containing lansoprazole-containinggranules, preferably, granules having an average particle size of about1000 μm to about 2000 μm are prepared by providing an intermediatecoating layer on a principal ingredient layer, which containslansoprazole in an amount of about 14% by weight to about 20% by weightbased on the total granules and a basic salt of magnesium and/or calciumin an amount of about 0.2 part by weight to about 0.4 part by weightbased on 1 part by weight of lansoprazole, and then providing an entericcoating layer thereon, and the granules are filled in a capsule. As acapsule containing 30 mg of lansoprazole per capsule, conventionalproducts are No.1 to No.2 capsules, while No.3 to No.5 stable capsulescan be produced according to the present invention. In addition, in caseof a capsule containing 15 mg of lansoprazole per capsule in which theabove granules are filled, it is possible to reduce the size to No.4 toNo.5 capsules. Further, in case of a capsule containing 60 mg oflansoprazole R isomer, No.3 to No. 1 capsules are possible. Furthermore,in case of a capsule containing 40 mg, No.4 to No.2 capsules arepossible and, in case of a capsule containing 30 mg, No.5 to No.3capsules are possible.

In the granules of the present invention, since PPI such as thebenzimidazole compound has excellent antiulcer activity, gastric acidsecretion inhibiting activity, mucosa protecting activity,anti-Helicobacter pylori activity and the like, and has low toxicity,they are useful for medicine. In this case, the granules of the presentinvention can be administered to a mammal (e.g. human, monkey, sheep,horse, dog, cat, rabbit, rat, mouse, etc.) orally for the purpose oftreating and preventing peptic ulcers (e.g. gastric ulcer, duodenalulcer, stomal ulcer, etc.), Zollinger-Ellison syndromes, gastritis,reflux esophagitis, symptomatic gastroesophageal reflux disease(symptomatic GERD)), NUD (non ulcer dyspepsia), stomach cancer(including stomach cancer accompanied with promotion of production ofinterleukin-1β due to genetic polymorphism of interleukin-1), gastricMALT lymphoma and the like, eradicating Helicobacter pylori, suppressingupper gastrointestinal hemorrhage due to peptic ulcers, acute stressulcer and hemorrhagic gastritis, suppressing upper digestive tracthemorrhagic due to invasion stress (stress resulting from majoroperation requiring post-operative intensive management, andcerebrovascular disorder, head trauma, multiple organ failure anddiffuse burn requiring intensive care), treating and preventing ulcersresulting from nonsteroidal antiinflammatory medicaments; treating andpreventing excess stomach acid and ulcer due to post-operation stress,and the like. For eradicating Helicobacter pylori, etc., the granules orcapsule of the present invention may be used together with other activecomponent(s) (e.g. 1 to 3 active component(s)).

Examples of the “other active component(s)” include anti-Helicobacterpylori active substances, antimicrobial agents such as imidazolecompounds, quinolone compounds, and bismuth salts. Inter alia, medicinescomprising a combination of the granules or capsule of the presentinvention and an antimicrobial agent are preferred. Among them, acombination with anti-Helicobacter pylori active substances, orantimicrobial agents such as imidazole compounds is preferred. Examplesof the “anti-Helicobacter pylori active substance” include penicillinantibiotics (e.g. amoxicillin, benzylpenicillin, piperacillin,mecillinam, etc.), cephem antibiotics (e.g. cefixime, cefaclor, etc.),macrolide antibiotics (e.g. erythromycin antibiotics such aserythromycin, clarithromycin, etc.), tetracycline antibiotics (e.g.tetracycline, minocycline, streptomycin, etc.), aminoglycosideantibiotics (e.g. gentamycin, amikacin, etc.), imipenem and the like.Inter alia, penicillin antibiotics and macrolide antibiotics arepreferred.

Examples of the “imidazole compound” include metronidazole, miconazole,etc. Examples of the “bismuth salt” include bismuth acetate, bismuthcitrate, etc. Antibacterial agents of “quinolone compounds” are alsopreferred, and examples thereof include ofloxacin, ciprofloxacin, etc.Inter alia, for eradicating Helicobacter pylori, it is preferred to usethe granules or capsule of the present invention in combination withpenicillin antibiotics (e.g. amoxicillin, etc.) and/or erythromycinantibiotics (e.g. clarithromycin etc.).

For example, in case of lansoprazole, in many cases, a conventional 15mg-containing capsule is a product filled in a No.3 capsule, and aconventional 30 mg-containing capsule is a product filled in a No.1capsule. However, according to the present invention, since the amountsof components other than a basis can be reduced without deterioratingstability of the basis and a preparation, the size of a 15 mg-containingcapsule can be reduced to No.4 to No.5 capsules, and the size of a 30mg-containing capsule can be reduced to No.3 to No.5 capsules,respectively.

Further, even in a 60 mg-containing capsule, it is possible to use No.1to No.3 capsules.

Furthermore, in case of an optically active isomer of lansoprazole, No.3to No.5 capsules, No.2 to No.4 capsules and No.1 to No.3 capsules can beused for 30 mg-, 40 mg- and 60 mg-containing capsules, respectively.

For example, because of a high content of an active component and easyadministration, a capsule containing 60 mg of lansoprazole orlansoprazole R isomer is suitable for treating, inter alia, acidhypersecretion symptom including Zollinger-Ellison syndromes.

A daily dosage varies depending on the degree of symptom, the age, sexand weight of subject, the administration time, interval, and the kindof principal or active ingredient, etc., and is not specificallylimited. For example, when orally administered to an adult (60 kg) as anantiulcer agent, a dosage is about 0.5 to 1500 mg/day, preferably about5 to 150 mg/day in terms of an active component. These benzimidazolecompound-containing preparations may be administered once or by dividinginto 2 to 3 times daily.

Hereinafter, the present invention will be illustrated in more detail byExamples, but the present invention is not limited by them. In thefollowing Examples, lansoprazole and its optically active isomer in theform of crystals were used.

EXAMPLE 1

Lansoprazole, magnesium carbonate, sucrose (pulverized sucrose), cornstarch and low-substituted hydroxypropylcellulose were thoroughly mixedto obtain a spreading mixture of principal ingredient. Sphericalgranules consisting of sucrose and starch were placed in an agitatorfluidized granulation coating machine (MP-10 manufactured by Powlex),and the above spreading mixture of principal ingredient was coated whilespraying a hydroxypropylcellulose solution (2.5%: W/W) to obtainspherical granules. The resultant spherical granules were dried in avacuum at 40° C. for 16 hours, and passed through a round sieve toobtain granules of 500 μm to 1180 μm. Granules Composition in 150 mgSpherical granules consisting of 50 mg sucrose and starch Lansoprazole30 mg Magnesium carbonate 10 mg Sucrose (pulverized sucrose) 30 mg Cornstarch 14 mg Low-substituted hydroxypropylcellulose 15 mgHydroxypropylcellulose 1 mg Purified water 39 μl Total 150 mg

An enteric suspension having the following composition was coated on theabove granules using an agitator fluidized granulation coating machine(MP-10, manufactured by Powlex), which were dried as such, and passedthrough a round sieve to obtain enteric granules of 710 to 1420 μm. Intothe resultant granules were mixed talc and aerosil, and 190 mg of theresultant mixed granules were filled into a No.3 capsule manually.Composition of enteric suspension Methacrylic acid copolymer 86.7 mg(solid components 26 mg) Talc 7.8 mg Polyethylene glycol 2.5 mg Titaniumoxide 2.5 mg Polysorbate 80 1.0 mg Purified water 119.5 μl Total 39.8 mg(as solids) Composition of enteric granules Granules 150 mg Entericcoating layer 39.8 mg Total 189.8 mg Composition of mixed granulesEnteric granules 189.8 mg Talc 0.1 mg Aerosil 0.1 mg Total 190 mgComposition of capsule Mixed granules 190 mg No. 3 capsule 1

In addition, particle size distribution of the resultant mixed granuleswas measured using a round sieve, and the results are shown below: 1180μm remaining 10.6% 1180/1000 μm 70.9% 1000/850 μm 12.0%  850 μm pass6.4%

EXAMPLE 2

Lansoprazole, magnesium carbonate, sucrose (pulverized sucrose), cornstarch and low-substituted hydroxypropylcellulose were thoroughly mixedto obtain a spreading mixture of principle ingredient. Sucrose(pulverized sucrose), corn starch and low-substitutedhydroxypropylcellulose were thoroughly mixed to obtain a spreadingmixture for intermediate layer. Spherical granules consisting of sucroseand starch were placed in a centrifugal Fluid-bed granulator (CF-360φmanufactured by Freund), and the above spreading mixture of principalingredient and the spreading mixture for intermediate layer were coatedwhile spraying a hydroxypropylcellulose solution (2.5%: W/W) to obtainspherical granules. The resultant spherical granules were dried in avacuum at 40° C. for 16 hours, and passed through a round sieve toobtain granules of 500 μm to 1180 μm. Granules Composition in 160 mgSpherical granules consisting of 50 mg sucrose and starch Spreadingmixture of principal ingredient Lansoprazole 30 mg Magnesium carbonate10 mg Sucrose (pulverized sucrose) 30 mg Corn starch 14 mgLow-substituted hydroxypropylcellulose 15 mg Spreading mixture forintermediate layer Sucrose (pulverized sucrose) 5 mg Corn starch 2.5 mgLow-substituted hydroxypropylcellulose 2.5 mg Binder solutionHydroxypropylcellulose 1 mg Purified water 34 μl Total 160 mg

An enteric suspension having the following composition was coated on theabove granules using an agitator fluidized granulation coating machine(MP-10 manufactured by Powlex), which was dried as such, and passedthrough a round sieve to obtain enteric granules of 600 to 1420 μm. Intothe resultant granules were mixed talc and aerosil, and 200 mg of theresultant mixed granules were filled into a No.3 capsule. Composition ofenteric suspension Methacrylic acid copolymer 86.7 mg (solid components26 mg) Talc 7.8 mg Polyethylene glycol 2.5 mg Titanium oxide 2.5 mgPolysorbate 80 1.0 mg Purified water 119.5 μl Total 39.8 mg (as solids)Composition of enteric granules Granules 160 mg Enteric coating layer39.8 mg Total 199.8 mg Composition of mixed granules Enteric granules199.8 mg Talc 0.1 mg Aerosil 0.1 mg Total 200 mg Composition of capsuleMixed granules 200 mg No. 3 capsule 1

In addition, particle size distribution of the resultant mixed granuleswas measured using a round sieve, and the results are shown below: 1180μm remaining 20.2% 1180/1000 μm 76.2% 1000/850 μm 3.6%  850/710 μm 0.0% 710 μm passed 0.0%

EXAMPLE 3

A suspension was prepared by using lansoprazole, magnesium carbonate,low-substituted hydroxypropylcellulose, hydroxypropylcellulose andpurified water. Microcrystalline cellulose spherical granules wereplaced in an agitator fluidized granulation coating machine (MP-10manufactured by Powlex), and the suspension was coated while sprayingthe suspension to obtain spherical granules. The granules were dried assuch, and passed through a round sieve to obtain granules of 500 μm to1180 μm. Granules Composition in 70 mg Microcrystalline cellulosespherical 20 mg granules Lansoprazole 30 mg Magnesium carbonate 10 mgLow-substituted hydroxypropylcellulose 5 mg Hydroxypropylcellulose 5 mgPurified water 100 μl Total 70 mg

An intermediate layer suspension was prepared by usinghydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose,D-mannitol and purified water. The granules containing lansoprazole wereplaced in an agitator fluidized granulation coating machine (MP-10manufactured by Powlex), and an intermediate layer was coated whilespraying the suspension to obtain spherical granules. The granules weredried as such and passed through a round sieve to obtain granules of 500μm to 1800 μm. Granules Composition in 80 mg Lansoprazole-containinggranules 70 mg Hydroxypropylmethylcellulose 5 mg Low-substitutedhydroxypropylcellulose 2.5 mg D-mannitol 2.5 mg Purified water 40 μlTotal 80 mg

An enteric suspension having the following composition was coated on theabove granules using an agitator fluidized granulation coating machine(MP-10 manufactured by Powlex), which was dried as such, and passedthrough a round sieve to obtain enteric granules of 600 to 1420 μm. Intothe resultant granules were mixed talc and aerosil, and 100 mg of theresultant mixed granules were filled in a No. 5 capsule. Composition ofenteric suspension Methacrylic acid copolymer 43.3 mg (solid components13 mg) Talc 3.8 mg Polyethylene glycol 1.2 mg Titanium oxide 1.2 mgPolysorbate 80 0.5 mg Purified water 60 μl Total 19.7 mg (as solids)Composition of enteric granules Granules 80 mg Enteric coating layer19.7 mg Total 99.7 mg Composition of mixed granules Enteric granules99.7 mg Talc 0.2 mg Aerosil 0.1 mg Total 100 mg Composition of capsuleMixed granules 100 mg No. 5 capsule 1

In addition, particle size distribution of the resultant mixed granuleswas measured using a round sieve, and the results are shown below: 1180μm remaining 5.6% 1180/1000 μm 91.3% 1000/850 μm 3.1%  850 μm passed0.0%

EXAMPLE 4

Lansoprazole, magnesium carbonate, sucrose (pulverized sucrose), cornstarch, low-substituted hydroxypropylcellulose andhydroxypropylcellulose were thoroughly mixed to obtain a spreadingmixture of principal ingredient. Sucrose (pulverized sucrose), cornstarch, low-substituted hydroxypropylcellulose andhydroxypropylcellulose were thoroughly mixed to obtain a spreadingmixture for intermediate layer. Spherical granules consisting of sucroseand starch were placed in a centrifugal Fluid-bed granulator (CF-1300φmanufactured by Freund) and the above spreading mixture of principalingredient and the spreading mixture for intermediate layer were coatedwhile spraying purified water to obtain spherical granules. Theresultant spherical granules were dried in a vacuum at 45° C. for 18hours, and passed through a vibrating screen to obtain granules of 500μm to 1180 μm. Granules Composition in 320 mg Spherical granulesconsisting of  100 mg sucrose and starch Spreading mixture of principalingredient Lansoprazole   60 mg Magnesium carbonate   20 mg Sucrose(pulverized sucrose)   60 mg Corn starch   28 mg Low-substitutedhydroxypropylcellulose   30 mg Hydroxypropylcellulose  1.8 mg Spreadingmixture for intermediate layer Sucrose (pulverized sucrose)   10 mgHydroxypropylcellulose  0.2 mg Purified water   60 μl Total  320 mg

An enteric suspension having the following composition was coated on theabove granules using a fluidized bed coating machine (FLO-90manufactured by Freund), which was dried as such, and passed through avibrating screen to obtain enteric granules of 600 to 1420 μm. To theresultant granule were mixed talc and aerosil using a tumbler mixer(manufactured by Showa Kagakukikai-kousakusho, 1300 L), and 400 mg ofthe resultant mixed granules were filled in a No. 1 capsule using acapsule filler (MATIC-90 manufactured by IMA). Composition of entericsuspension Methacrylic acid copolymer 173.4 mg (solid components   52mg) Talc  15.6 mg Polyethylene glycol  5.0 mg Titanium oxide  5.0 mgPolysorbate 80  2.0 mg Purified water   239 μl Total  79.6 mg (assolids) Composition of enteric granules Granules   320 mg Entericcoating layer  79.6 mg Total 399.6 mg Composition of mixed granulesEnteric granules 399.6 mg Talc  0.2 mg Aerosil  0.2 mg Total   400 mgComposition of capsule Mixed granules   400 mg No. 1 capsule 1

In addition, particle size distribution of the resultant mixed granuleswas measured using a round sieve, and the results are shown below: 1180μm remaining 2.6% 1180/1000 μm 92.2% 1000/850 μm 4.6% 850/710 μm 0.4%710 μm passed 0.2%

EXAMPLE 5

A composition is shown in Table 1. Lansoprazole R isomer, magnesiumcarbonate, sucrose (pulverized sucrose), corn starch and low-substitutedhydroxypropylcellulose were thoroughly mixed to obtain a spreadingmixture of principal ingredient. In addition, sucrose (pulverizedsucrose), corn starch and low-substituted hydroxypropylcellulose werethoroughly mixed to obtain a spreading mixture of intermediate layer.Spherical granulates consisting of sucrose and starch were placed in acentrifugal Fluid-bed granulator (CF manufactured by Freund), and theabove spreading mixture of principal ingredient and the spreadingmixture for intermediate layer were successively coated while spraying ahydroxypropylcellulose solution (2%: W/W) to obtain spherical granules.The coating operation conditions were as follows: rotor rotating speed:300 rpm, spray rate: 1.8 g/min, spray air pressure: 0.2 kg/cm², and slitair pressure: 0.2 kg/cm². The resultant spherical granules were dried ina vacuum at 40° C. for 20 hours and passed through a round sieve toobtain granules of 710 μm to 1420 μm.

An enteric suspension was coated on the above granules using a fluidizedgranulation coating machine (LAB-1 manufactured by Powlex), which wasdried as such, and passed through a round sieve to obtain entericgranules of 850 to 1420 μm. The coating operation conditions were asfollows: inlet air volume: 0.6 m³/min, inlet air temperature: 85° C.,spray rate: 8 g/min, and spray air pressure: 1 kg/cm².

Into the resultant granules were mixed talc and aerosil, and 150 mg(corresponding to 30 mg of lansoprazole R isomer), 200 mg (correspondingto 40 mg of lansoprazole R isomer) and 300 mg (corresponding to 60 mg oflansoprazole R isomer) of the resultant mixed granules were filled inNo. 4, No. 3 and No. 2 capsules, respectively.

EXAMPLE 6

A composition is shown in Table 1. Lansoprazole R isomer, magnesiumcarbonate, sucrose (pulverized sucrose) and low-substitutedhydroxypropylcellulose were thoroughly mixed to obtain a spreadingmixture of principal ingredient. In addition, sucrose (pulverizedsucrose), low-substituted hydroxypropylcellulose and titanium oxide werethoroughly mixed to obtain a spreading mixture for intermediate layer.Spherical granules consisting of sucrose and starch were placed in acentrifugal Fluid-bed granulator (CF manufactured by Freund), the abovespreading mixture of principal ingredient and the spreading mixture forintermediate layer were successively coated while spraying ahydroxypropylcellulose solution (2%: W/W) to obtain spherical granules.The coating operation conditions were as follows: rotor rotating speed:300 rpm, spray rate: 1.8 g/min, spray air pressure: 0.2 kg/cm², and slitair pressure: 0.2 kg/cm². The resultant spherical granules were dried ina vacuum at 40° C. for 20 hours, and passed through a round sieve toobtain granules of 710 μm to 1420 μm.

An enteric suspension was coated on the above granules using a fluidizedgranulation coating machine (LAB-1 manufactured by Powlex), which wasdried as such, and passed through a round sieve to obtain entericgranules of 850 to 1420 μm. The coating operation conditions were asfollows: inlet air volume: 0.6 m³/min, inlet air temperature: 85° C.,spray rate: 8 g/min, and spray air pressure: 1 kg/cm².

Into the resultant granules were mixed talc and aerosil, and 150 mg(corresponding to 30 mg of lansoprazole R isomer), 200 mg (correspondingto 40 mg of lansoprazole R isomer) and 300 mg (corresponding to 60 mg oflansoprazole R isomer) of the resultant mixed granules were filled inNo. 4, No. 3 and No. 2 capsules, respectively.

EXAMPLE 7

A composition is shown in Table 1. Lansoprazole R isomer, magnesiumcarbonate, sucrose (pulverized sucrose), low-substitutedhydroxypropylcellulose and titanium oxide were thoroughly mixed toobtain a spreading mixture of principal ingredient. Spherical granulesconsisting of sucrose and starch were placed in a centrifugal Fluid-bedgranulator (CF manufactured by Freund), and the above spreading mixtureof principal ingredient was coated while spraying ahydroxypropylcellulose solution (2%: W/W) to obtain spherical granules.The coating operation conditions were as follows: rotor rotating speed:300 rpm, spray rate: 1.8 g/min, spray air pressure: 0.2 kg/cm², and slitair pressure: 0.2 kg/cm². The resultant spherical granules were dried ina vacuum at 40° C. for 20 hours, and passed through a round sieve toobtain granules of 710 μm to 1420 μm.

An enteric suspension was coated on the above granules using a fluidizedgranulation coating machine (LAB-1 manufactured by Powlex), which wasdried as such, and passed though a round sieve to obtain entericgranules of 850 to 1420 μm. The coating operation conditions were asfollows: inlet air volume: 0.6 m³/min, inlet air temperature: 85° C.,spray rate: 8 g/min, and spray air pressure: 1 kg/cm².

Into the resultant granules were mixed talc and aerosil, and 150 mg(corresponding to 30 mg of lansoprazole R isomer), 200 mg (correspondingto 40 mg of lansoprazole R isomer) and 300 mg (corresponding to 60 mg oflansoprazole R isomer) of the resultant mixed granules were filled inNo. 4, No. 3 and No. 2 capsules, respectively. TABLE 1 Composition tableGranules Composition in 160 mg Example 5 Example 6 Example 7 Sphericalgranules   50 mg  50 mg   50 mg consisting of sucrose and starchSpreading mixture of principal ingredient Lansoprazole R isomer   40 mg 40 mg   40 mg Magnesium carbonate   14 mg  14 mg   14 mg Sucrose(pulverized   26 mg  26 mg   36 mg sucrose) Corn starch   9 mg   0 mg  0 mg Low-substituted   10 mg  10 mg 12.5 mg hydroxypropylcelluloseTitanium oxide   0 mg   0 mg  6.5 mg Spreading mixture for intermediatelayer Sucrose (pulverized   5 mg  10 mg sucrose) Corn starch  2.5 mg   0mg Low-substituted  2.5 mg 2.5 mg hydroxypropylcellulose Titanium oxide  0 mg 6.5 mg Binder solution Hydroxypropylcellulose   1 mg   1 mg   1mg Purified water   49 μl  49 μl   49 μl Total  160 mg Composition ofenteric suspension Methacrylic acid  86.7 mg (solid components 26 mg)copolymer Talc  7.8 mg Polyethylene glycol  2.5 mg Titanium oxide  2.5mg Polysorbate 80  1.0 mg Purified water 119.5 μl Total  39.8 mg (assolids) Composition of enteric granules Granules   160 mg Entericcoating layer  39.8 mg Total 199.8 mg Composition of mixed granulesEnteric granules 199.8 mg Talc  0.1 mg Aerosil  0.1 mg Total   200 mgComposition of capsules Lansoprazole corresponding correspondingcorresponding R isomer to 30 mg to 40 mg to 60 mg Mixed 150 mg 200 mg300 mg granules Capsule 1 (No. 4) 1 (No. 3) 1 (No. 2)

EXAMPLE 8

A composition is shown in Table 2. Lansoprazole R isomer, magnesiumcarbonate, sucrose (pulverized sucrose), corn starch and low-substitutedhydroxypropylcellulose were thoroughly mixed to obtain a spreadingmixture of principal ingredient. In addition, sucrose (pulverizedsucrose), corn starch and low-substituted hydroxypropylcellulose werethoroughly mixed to obtain a spreading mixture for overcoating.Spherical granules consisting of sucrose and starch were placed in acentrifugal Fluid-bed granulator (CF manufactured by Freund), and theabove spreading mixture of principal ingredient was successively coatedwhile spraying a hydroxypropylcellulose solution (2%: W/W) to obtainspherical granules. The coating operation conditions were as follows:rotor rotating speed: 300 rpm, spray rate: 1.8 g/min, spray airpressure: 0.2 kg/cm², and slit air pressure: 0.2 kg/cm². The resultantspherical granules were dried in a vacuum at 40° C. for 20 hours, andpassed through a round sieve to obtain granules of 710 μm to 1420 μm.

A suspension composed of hydroxypropylmethylcellulose, titanium oxideand purified water shown in Table 2 was prepared. This suspension wascoated on the above granules using a fluidized granulation coatingmachine (LAB-1 manufactured by Powlex), which was dried as such, andpassed through a round sieve to obtain enteric granules of 850 to 1420μm. The coating operation conditions were as follows: inlet air rate:0.8 to 1 m³/min, inlet air temperature: 85° C., spray rate: 6 g/min, andspray air pressure: 0.8 to 1 kg/cm².

An enteric suspension was coated on the above granules using a fluidizedgranulation coating machine (LAB-1 manufactured by Powlex), which wasdried as such, and passed through a round sieve to obtain entericgranules of 850 to 1420 μm. The coating operation conditions were asfollows: inlet air rate: 0.6 m³/min, inlet air temperature: 85° C.,spray rate: 8 g/min, and spray air pressure: 1 kg/cm².

Into the resultant granules were mixed talc and aerosil, and 150 mg(corresponding to 30 mg of lansoprazole R isomer), 200 mg (correspondingto 40 mg of lansoprazole R isomer) and 300 mg (corresponding to 60 mg oflansoprazole R isomer) of the resultant mixed granules were filled intoNo. 4, No. 3 and No. 2 capsules, respectively. TABLE 2 Composition tableGranules Composition in 141 mg Spherical granules consisting of   50 mgsucrose and starch Spreading mixture of principal ingredientLansoprazole R isomer   40 mg Magnesium carbonate   14 mg Sucrose(pulverized sucrose)   26 mg Low-substituted   10 mghydroxypropylcellulose Binder solution Hydroxypropylcellulose    1 mgPurified water   49 μl Total   141 mg Composition of intermediate layersuspension Hydroxypropylmethylcellulose  12.5 mg Titanium oxide  6.5 mgPurified water   171 μl Total   19 mg (as solids) Composition ofintermediate layer coated granules Granules   141 mg Intermediate layercoating   19 mg Total   160 mg Composition of enteric suspensionMethacrylic acid copolymer  86.7 mg (solid components   26 mg) Talc  7.8mg Polyethylene glycol  2.5 mg Titanium oxide  2.5 mg Polysorbate 80 1.0 mg Purified water 119.5 μl Total  39.8 mg (as solids) Compositionof enteric granules Granules   160 mg Enteric coating layer  39.8 mgTotal 199.8 mg Composition of mixed granules Enteric granules 199.8 mgTalc  0.1 mg Aerosil  0.1 mg Total   200 mg Composition of capsulesLansoprazole  30 mg  40 mg  60 mg R isomer equivalent equivalentequivalent Mixed 150 mg 200 mg 300 mg granules Capsule 1 (No. 4) 1 (No.3) 1 (No. 2)Experiment 1

Each of the enteric granules (mixed granules) prepared in Examples 1 and2 was stored in a tightly sealed bottle under 40° C./75% RH for 24 weeksand, thereafter, a content (remaining rate) and appearance change (ΔE)were measured. The content was measured by HPLC method. Appearancechange (ΔE) was obtained by measuring a color difference (ΔE) using SMcolor computer SM-5 (manufactured by Suga Shikenki). The results areshown in Table 3. TABLE 3 Example 1 Example 2 Content Content (remaining(remaining Storing conditions ΔE rate) ΔE rate) Initial —   100% —  100% 40° C. 75% RH tightly 1.73 100.0% 2.84  99.7% sealed 4 W 40° C.75% RH tightly 7.27 100.0% 3.79  99.9% sealed 12 W 40° C. 75% RH tightly3.88  98.7% 5.06 100.4% sealed 24 W

As a result, it was revealed that the granules of the present inventionhad less appearance change and stable content.

Experiment 2

Each of the enteric granules (mixed granules) prepared in Examples 5 to8 was stored in a tightly sealed glass bottle at 60° C. for 2 weeks and,thereafter, a content (remaining rate) was measured. The content wasmeasured by HPLC method. The results are shown in Table 4. Appearancechange of the preparations of Examples 7 and 8 was hardly observed withnaked eyes. TABLE 4 Results of stability test of Examples 5 to 8 Storingconditions: 60° C. tightly sealed glass bottle, 2 weeks storage Content(remaining Example rate) Example 5 97.8% Example 6 97.1% Example 7 95.9%Example 8 99.1%

As a result, it was revealed that the granules of the present inventionare stable from a viewpoint of the content.

INDUSTRIAL APPLICABILITY

By optimizing a blending ratio of a basic inorganic salt with anacid-unstable medicament, in particular, a benzimidazole compound, andan average particle size, unexpectedly, the granules of the presentinvention enabled the acid-unstable medicament to be stable even at highconcentration and high content. In addition, since the granules of thepresent invention contains an active ingredient at high concentration,the amount of a whole preparation can be reduced even at the samecontent and, therefore, the size of a capsule or the like can bereduced, and a preparation which can be easily administered can beobtained. As a result, the preparation can be easily administered topatients, in particular, elderly and pediatric patients who havedifficulty in swallowing, and compliance can be improved.

1. Granules comprising a principal ingredient layer containing anacid-unstable medicament in an amount of about 12% by weight or morebased on the total granules; an intermediate coating layer which isformed on the principal ingredient layer; and an enteric coating layerwhich is formed on the intermediate coating layer; wherein said granulescontain a basic inorganic salt, and have an average particle size ofabout 600 μm or more.
 2. The granules according to claim 1, wherein thebasic inorganic salt is a magnesium salt or a calcium salt.
 3. Thegranules according to claim 1, wherein the acid-unstable medicament is aproton pump inhibitor (PPI).
 4. The granules according to claim 3,wherein the PPI is a benzimidazole compound represented by the formula(I):

wherein ring A is an optionally substituted benzene ring, R¹, R² and R³are the same or different, and represent a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted alkoxy group, or anoptionally substituted amino group, and Y represents a nitrogen atom orCH, or a salt thereof.
 5. The granules according to claim 3, wherein thePPI is lansoprazole, omeprazole, rabeprazole, pantoprazole,leminoprazole, tenatoprazole (TU-199), or an optically active isomerthereof, or a pharmaceutically acceptable salt thereof.
 6. The granulesaccording to claim 3, wherein the PPI is lansoprazole, or an opticallyactive isomer thereof, or a pharmaceutically acceptable salt thereof. 7.The granules according to claim 4, wherein the basic inorganic salt iscontained in the principal ingredient layer in an amount of about 0.2part by weight to about 0.6 part by weight based on 1 part by weight ofthe benzimidazole compound.
 8. The granules according to claim 1 whichare granules having a core, wherein the principal ingredient layer isformed on the core comprising at least one material selected fromsucrose, starch, lactose and crystalline cellulose.
 9. The granulesaccording to claim 1, wherein the enteric coating layer contains anenteric water-soluble polymer.
 10. The granules according to claim 9,wherein the enteric water-soluble polymer is a methacrylic acidcopolymer.
 11. The granules according to claim 1, wherein an averageparticle size of the granules is about 1000 μm to about 2000 μm.
 12. Thegranules according to claim 4, wherein the benzimidazole compound iscontained in an amount of about 12% by weight to about 40% by weightbased on the total granules.
 13. A granular preparation, a capsule, atablet, an effervescent preparation or a suspension comprising thegranules according to claim
 1. 14. Granules comprising a principalingredient layer containing a PPI in an amount of about 12% by weight toabout 40% by weight based on the total granules, and one or more basicinorganic salts selected from the group consisting of basic salts of asodium salt, a potassium salt, an aluminum salt, a magnesium salt and acalcium salt in an amount of about 0.2 part by weight to about 0.6 partby weight based on 1 part by weight of the PPI; an intermediate coatinglayer which is formed on the principal ingredient layer; and an entericcoating layer which is formed on the intermediate coating layer, andhaving an average particle size of about 1000 μm to about 2000 μm.
 15. Agranular preparation, a capsule or a tablet comprising the granulesaccording to claim
 14. 16. The preparation according to claim 15, whichis a preparation for treating or preventing peptic ulcer,Zollinger-Ellison syndromes, gastritis, reflux esophagitis, symptomaticgastroesophageal reflux disease (symptomatic GERD), NUD (non ulcerdyspepsia), stomach cancer, gastric MALT lymphoma, ulcer resulting fromnonsteroidal antiinflammatory medicaments, or excess stomach acid orulcer due to post-operation stress, a preparation for eradicatingHelicobacter pylori, or a preparation for suppressing uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasion stress.
 17. Granules comprising aprincipal ingredient layer containing lansoprazole or an opticallyactive isomer (R isomer) thereof in an amount of about 14% by weight toabout 20% by weight based on the total granules, and one or more basicinorganic salts selected from the group consisting of basic salts ofmagnesium and calcium in an amount of about 0.2 part by weight to about0.4 part by weight based on 1 part by weight of lansoprazole or anoptically active isomer (R isomer) thereof; an intermediate coatinglayer which is formed on the principal ingredient layer; and an entericcoating layer which is formed on the intermediate coating layer, andhaving an average particle size of 1000 μm to about 2000 μm.
 18. Thegranules according to claim 17, wherein the basic inorganic salt ismagnesium carbonate.
 19. No. 3 to 5 capsules comprising 30 mg oflansoprazole per one capsule.
 20. No. 3 to 5 capsules comprising 30 mgof lansoprazole per one capsule, wherein the granules according to claim17 are filled.
 21. No. 4 to 5 capsules comprising 15 mg of lansoprazoleper one capsule.
 22. No. 4 to 5 capsules comprising 15 mg oflansoprazole per one capsule, wherein the granules according to claim 17are filled.
 23. No. 1 to 3 capsules comprising 60 mg of lansoprazole oran optically active isomer (R isomer) thereof per one capsule.
 24. No. 1to 3 capsules comprising 60 mg of lansoprazole or an optically activeisomer (R isomer) thereof per one capsule, wherein the granule accordingto claim 17 is filled.
 25. No. 2 to 4 capsules comprising 40 mg of anoptically active isomer (R isomer) of lansoprazole per one capsule. 26.No. 2 to 4 capsules comprising 40 mg of an optically active isomer (Risomer) of lansoprazole per one capsule, wherein the granules accordingto claim 17 are filled.
 27. No. 3 to 5 capsules comprising 30 mg of anoptically active isomer (R isomer) of lansoprazole per capsule.
 28. No.3 to 5 capsules comprising 30 mg of an optically active isomer (Risomer) of lansoprazole per capsule, wherein the granules as defined inclaim 17 are filled.
 29. A pharmaceutical composition which is acombination of an antimicrobial agent and the granules according toclaim 3.